The existence of a relationship between cutaneous T cell lymphoma (CTCL) and chronic stimulation of the immune system has been postulated for many years (Tan et al., 1974, British J. Dermatol. 91:607–616). A report by Duvic and co-workers (Jackow et al., 1997, Blood 89:32–40) has suggested an association between Staphylococcus aureus infection and CTCL. The report proposes that S. aureus provides chronic stimulation of the immune cells in CTCL patients, and that such stimulation may exacerbate the CTCL disease process. It is well established that a bacterial infection in the epidermis (i.e., skin) can lead to the production of inflammatory cytokines, resulting initially in lymphocytic infiltration and release of IFN-γ, followed by IL-10 production, and clonal expansion of epidermotropic T cells (Sarris et al., 1995, Blood 86:651–658). The Duvic report has added to the understanding of CTCL by providing a rational mechanism by which a bacterium could stimulate lymphocytic infiltration and promote chronic stimulation in CTCL patients.
The relationship between CTCL and Chlamydia pneumoniae infection has not been investigated. C. pneumoniae is an obligate intracellular pathogen that replicates within the cytoplasm of the cells in that it infects. C. pneumoniae was originally described as a respiratory pathogen (Leinonen, 1993, Eur. Heart J. 14: Supplement K, 57–61). However, the organism has been implicated in several non-pulmonary diseases such as meningoencephalitis, atherosclerosis and Alzheimer's disease (Campbell et al., 1995, J. Infect. Dis. 172:585–588; Gran et al., 1993, Scand. J. Rheumatol. 22:43–44; Koskiniemi et al., 1996, Eur. Neurol. 36:160–163; Balin et al., 1998, Med. Micro. & Immunol. 187:23–42). Epidemiological studies indicate that infection of adults by C. pneumoniae is common in all populations examined (Grayston, 1992, Annu. Rev. Med. 43:317–23; Hyman et al., 1995, Clin. Infect. Dis. 20:1174–1178; Leinonen, 1993, Eur. Heart J. 14: Supplement K, 57–61). Detection of significant anti-C. pneumoniae antibody titers rises with increasing age, with antibody levels peaking in the 6th–7th decades in most populations (Leinonen, 1993, Eur. Heart J. 14 (Supplement K):57–61).
Immunopathology is a general feature of Chlamydia-induced disease. Because C. pneumoniae is an intracellular pathogen, the immune system has difficulty clearing the infection. Thus, persistent Chlamydial infections are common and result in chronic inflammation caused by the presence of Th1/Th2 CD4+ T cells, as well as CD8+ cytotoxic/suppressor T cells, macrophages, and in some cases, B cells (Whittum-Hudson et al., 1986, Curr. Eye Res. 5:973–979). An example of the result of persistent Chlamydial infection is observed in the synovia of C. trachomatis-induced reactive arthritis (Simon et al., 1993, Clin. Exp. Immunol. 94:122–126). Interestingly, persistent Chlamydial infection may be maintained in part by Chlamydial induction of the expression of host proteins such as interferons (Beatty et al., 1989, Proc. Natl. Acad. Sci. USA 90:3998–4002; Simon et al., 1993, Clin. Exp. Immunol. 94:122–126). Thus, a balance appears to develop between host tissue survival and Chlamydial replication. It has been suggested that such a state of semi-latency can last for decades (Beatty et al., 1989, Proc. Natl. Acad. Sci. USA 90:3998–4002; Koehler et al., 1997, Microbial Pathogenesis 22:133–142).
As it has been shown that C. pneumoniae can travel to numerous areas of the body (Balin et al., 1998, Med. Micro. & Immunol. 187:23–42; Campbell et al., 1995, J. Infect. Dis. 172:585–588; Gran et al., 1993, Scand. J. Rheumatol. 22:43–44; Koskiniemi et al., 1996, Eur. Neurol. 36:160–163; Leinonen, 1993, Eur. Heart J. 14 (Supplement K):57–61), the inventors have focused on whether C. pneumoniae antigens could be detected in cells within the epidermis in patients with mycosis fungoides, the primary form of CTCL, or in the peripheral blood mononuclear cells of patients with Sézary Syndrome, the leukemic variant of CTCL. Leukemic CTCL represents a malignant clonal amplification of mature immune cells, including memory (CD45R0+), epidermotropic (CTLA+), helper T cells (CD4+), and CD3+ T cells (Edelson, 1983, J. Am. Acad. Dermatol. 9:957–960; Fivenson et al., 1994, J. Amer. Acad. Dermatol. 31:717–723; Haynes et al., 1981, J. Clinic. Investig. 67:523–530; Hunt et al., 1992, J. Am Acad. of Dermatol. 26:5552–5558; Mielke et al., 1994, Dermatol. Clinics. 12:351–360; Sterry and Mielke, 1989, J. Investig. Dermatol. 93:413–416). These cell types predominantly produce a Th2 cytokine profile (Vowels et al., 1992, J. Investig. Dermatol. 99:90–94).
Previous investigations have also focused on identifying the growth requirements for malignant cells in CTCL. A stimulatory factor has been identified that is capable of inducing proliferation of malignant Sézary cells. This factor has been named Sézary T cell Activatin Factor, or SAF (Abrams et al., 1993, Can. Res. 53:5501–5506; DeFreitas and Abrams, U.S. Pat. No. 5,427,781). SAF was originally described as being produced by the peripheral blood mononuclear cells of certain patients with Sézary Syndrome (Abrams et al., 1991, J. Immunol. 146:1455–1462), and was found to be a potent T cell mitogenic factor for malignant as well as non-malignant T cells (Abrams et al., 1993, Can. Res. 53:5501–5506; Abrams et al., 1991, J. Investig. Dermatol. 96:31–37; Abrams et al, 1991, J. Immunol. 146:1455–1462). Accordingly, SAF has been used to establish cell lines from patients with Sézary Syndrome, some of which contained the predominant malignant clone (Abrams et al., 1991, J. Immunol. 146:1455–1462). SAF has enabled establishment of T cell lines from CTCL patients more readily than other methods (Gazdar et al., 1979, Cancer Treatment Rep. 63:587–590; Golstein et al., 1986, Scand. J. Immunol. 23:53–64). However, the role played by SAF in the development of CTCL remains to be elucidated.
CTCL represents a group of diseases for that distinct etiology is unknown and for which few effective treatments exist. In addition to understanding the mechanisms of CTCL pathology, there is a need to identify methods that are useful in identifying and treating CTCL. The present invention satisfies this need.